This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. The signal transduction pathways activated in glomerular mesangial cells by inflammatory cytokines and in renal tubular epithelial cells in response to ATP depletion are poorly understood. This is particularly true for pathways leading to the nucleus and the activation of the transcription factors controlling the genetic response to these stimuli. We have recently found that the Stress-activated protein kinase, or SAPKs, are activated in response to IL-1beta, and we have reported their activation by reperfusion of ischemic kidney and by reversible ATP depletion in MDCK cells. These kinases are the major c-Jun amino- terminal kinases activated by ischemia. Since phosphorylation of c-Jun within the amino-terminus is associated with increased trans acting activity, it is likely that the SAPKs are transducing an important ischemia-induced signal to the nucleus via activation of c-Jun. We have also found that ischemia and reversible ATP depletion activate ATF-2, a member of the CRE family of transcription factors which is activated by SAPK in vitro. Although these data suggest the SAPKs may be critical to the genetic response to ischemia and reversible ATP depletion, the pathways of activation of these kinases and their role in activating transcription remain unclear. The specific goals of the proposal are: Specific Aim 1. Characterize the pathways of activation of the SAPKs in response to IL-1beta. We propose to characterize this signalling pathway, starting from the IL-1 receptor and proceeding downstream toward the SAPKs using a variety of techniques, including the yeast interaction trap. Specific Aim 2. Determine the role of the SAPKs in the transcriptional response of cells to reversible ATP depletion and IL-1beta. We will examine effects of the SAPKs on ATF-2, and determine whether the SAPKs are responsible for the activation of transcription from defined promoters and from promoters of genes actually induced by IL-1beta or ATP depletion. Specific Aim 3. Determine the role f the SAPKs in the activation of cPLA2 by IL-1beta in mesangial cells. We propose that the SAPKs may be primarily responsible for cPLA2 activation in response to IL-1beta. The findings should more clearly define the role played by the SAPKs in the response of the kidney to inflammatory cytokines and energy depletion.